PROSPAX: an integrated multimodal progression chart in spastic ataxias

PROSPAX：痉挛性共济失调的综合多模式进展图

• 批准号: 441409627
• 负责人: Professorin Dr. Elena Irene Rugarli
• 金额: --
• 依托单位: Cluster of Excellence: Cellular Stress Responses in Aging-Associated Diseases
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/441409627?language=en
• 关键词: PROSPAX; integrated; multimodal; progression; chart

Spastic ataxias (SPAX) present an expanding group of >100 rare neurodegenerative diseases with joined damage of cerebellum and corticospinal tract (CST). While rapid genetic stratification facilitates current development of molecular therapies, effective trial-planning for SPAX is hampered by a lack of valid outcome measures and natural history studies. Uniting all major European ataxia and spastic paraplegia networks, and building on our prior networks and pilot data-sets, PROSPAX will establish a paradigmatic IRDiRC-guided integrated trial-ready model of disease progression and mechanistic evolution in SPAX, which will allow to track and understand selective as well as overlapping dysfunction of the cerebellum and CST. In a 2-year transatlantic natural history study we will longitudinally validate clinician- and patient-reported, digital and molecular outcomes. In addition, PROSPAX will improve on existing and develop new outcome parameters that show superior sensitivity to change. These include a novel clinical SPAX composite score, a smartphone mHealth toolbox combining remote assessment of daily living by wearable sensors with app-based patient-entered outcomes (SPAX.app), and multimodal MRI radiomics with an innovative machine learning approach for multisite MRI analysis, including in particular the infratentorial space. Longitudinal validation of targeted fluid biomarker candidates will be complemented by single-cell multi-omic studies in mouse which will allow to identify shared pathways and vulnerabilities between cerebellar and corticospinal neurons and will unravel new molecular biomarkers. By focusing on the two most prevalent recessive SPAX (SPG7, ARSACS), PROSPAX will create a paradigmatic trial-readiness pathway for charting disease progression and multimodal outcome measures that will be applicable to many of the >100 SPAX diseases alike.

痉挛性共济失调（SPAX）是一个不断扩大的群体，包括超过100种罕见的神经退行性疾病，伴有小脑和皮质脊髓束（CST）的联合损害。虽然快速的遗传分层促进了目前分子疗法的发展，但SPAX的有效试验计划受到缺乏有效结果指标和自然史研究的阻碍。结合所有主要的欧洲共济失调和痉挛性截瘫网络，并建立在我们以前的网络和试点数据集，PROSPAX将建立一个范例IRDiRC指导的综合试验准备模型的疾病进展和机制的演变在SPAX，这将允许跟踪和理解小脑和CST的选择性以及重叠功能障碍。在为期2年的跨大西洋自然史研究中，我们将纵向验证临床医生和患者报告的数字和分子结果。此外，PROSPAX将改进现有的和开发新的结果参数，显示出对变化的上级敏感性。其中包括一种新的临床SPAX综合评分，一种智能手机mHealth工具箱，将可穿戴传感器的日常生活远程评估与基于应用程序的患者输入结果（SPAX.app）相结合，以及多模态MRI放射组学与用于多部位MRI分析的创新机器学习方法，特别是幕下空间。靶向液体生物标志物候选物的纵向验证将通过小鼠中的单细胞多组学研究来补充，这将允许识别小脑和皮质脊髓神经元之间的共享途径和脆弱性，并将揭示新的分子生物标志物。通过关注两种最常见的隐性SPAX（SPG7，ARSACS），PROSPAX将创建一个典型的试验准备路径，用于绘制疾病进展和多模式结局指标，这些指标将适用于100种以上SPAX疾病中的许多疾病。